US5349068A - 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents - Google Patents

1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents Download PDF

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US5349068A
US5349068A US07/869,287 US86928792A US5349068A US 5349068 A US5349068 A US 5349068A US 86928792 A US86928792 A US 86928792A US 5349068 A US5349068 A US 5349068A
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Guy D. Diana
Theodore J. Nitz
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Sanofi Aventis France
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Sterling Winthrop Inc
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Priority to US07/869,287 priority Critical patent/US5349068A/en
Priority to TW082102383A priority patent/TW239140B/zh
Priority to CZ93597A priority patent/CZ285845B6/cs
Priority to MYPI93000665A priority patent/MY110191A/en
Priority to SG1996008085A priority patent/SG50663A1/en
Priority to PT93201058T priority patent/PT566199E/pt
Priority to ES93201058T priority patent/ES2143487T3/es
Priority to AT93201058T priority patent/ATE189958T1/de
Priority to EP93201058A priority patent/EP0566199B1/en
Priority to DE69327913T priority patent/DE69327913T2/de
Priority to DK93201058T priority patent/DK0566199T3/da
Priority to IL10537293A priority patent/IL105372A/en
Priority to NO19931366A priority patent/NO302700B1/no
Priority to RU93004675A priority patent/RU2114112C1/ru
Priority to KR1019930006244A priority patent/KR100314158B1/ko
Priority to PH46044A priority patent/PH30454A/en
Priority to CA002094012A priority patent/CA2094012C/en
Priority to HU9301084A priority patent/HU220606B1/hu
Priority to AU36881/93A priority patent/AU666528B2/en
Priority to MX9302169A priority patent/MX9302169A/es
Priority to JP05088647A priority patent/JP3103845B2/ja
Priority to NZ247411A priority patent/NZ247411A/en
Priority to FI931707A priority patent/FI112229B/fi
Priority to SK353-93A priority patent/SK279786B6/sk
Priority to UA93003099A priority patent/UA35557C2/uk
Priority to US08/131,050 priority patent/US5464848A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to novel 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles, to methods for the preparation thereof, and compositions and methods for the use thereof as antiviral agents.
  • R is hydrogen or lower-alkyl of 1-5 carbon atoms, with the proviso that when Z is N, R is lower-alkyl;
  • R 1 and R 2 are hydrogen, halogen, lower-alkyl, lower-alkoxy, nitro, lower-alkoxycarbonyl or trifluoromethyl;
  • Het is selected from specified heterocyclic groups. Included in the definition of Het is unsubstituted 1,3,4-oxadiazol-2-yl and unsubstituted 1,2,4-oxadiazol-5-yl.
  • Y is an alkylene bridge of 3 to 9 carbon atoms optionally interrupted by one or two oxygen atoms, by cyclohexyl or by an olefinic linkage;
  • X is O, S, SO or SO 2 ;
  • Z is N or R 8 C, where R 8 is hydrogen or lower-alkanoyl
  • R 1 and R 2 are selected from the group consisting of hydrogen, lower-alkyl, lower-alkenyl, halogen, nitro, lower-alkoxy, lower-alkylthio, difluoromethyl, trifluoromethyl, amino, lower-alkanoylamino, di-lower-alkylamino, hydroxy, lower-alkenoyl, lower-alkanoyl, hydroxymethyl and carboxy;
  • R and R 3 are each hydrogen or alkyl of 1 to 3 carbon atoms optionally substituted by a member of the group consisting of hydroxy, lower-alkanoyloxy, lower-alkoxy, halo or N ⁇ Z', wherein N ⁇ Z' is amino, lower-alkanoylamino, lower-alkylamino, di-lower-alkylamino, 1-pyrrolidyl, 1-piperidinyl or 4-morpholinyl; with the proviso that when Z is N, R is other than hydrogen; and
  • Het is selected from specified heterocyclic groups including unsubstituted 1,3,4-oxadiazol-2-yl.
  • R' is lower-alkyl or hydroxy-lower-alkyl of 1-5 carbon atoms
  • R 1 and R 2 are hydrogen, halogen, lower-alkyl, lower-alkoxy, nitro, lower-alkoxycarbonyl or trifluoromethyl;
  • R 8 is hydrogen or lower-alkyl of 1-5 carbon atoms.
  • R' is lower-alkyl or hydroxy-lower-alkyl of 1-5 carbon atoms
  • R 1 and R 2 are hydrogen, halogen, lower-alkyl, lower-alkoxy, nitro, lower-alkoxycarbonyl or trifluoromethyl;
  • R 8 is hydrogen or lower-alkyl of 1-5 carbon atoms.
  • R 1 is lower-alkyl, lower-alkoxy-(C 1-3 -alkyl), lower-alkoxycarbonyl, cyclopropyl or trifluoromethyl;
  • R 2 and R 3 independently are hydrogen, lower-alkyl, halogen, lower-alkoxy, nitro, trifluoromethyl or hydroxy;
  • R 4 is hydrogen or lower-alkyl; where lower-alkyl and lower-alkoxy, each occurrence, have from 1-5 carbon atoms;
  • R 1 when R 1 is lower-alkyl, at least one of R 2 and R 3 is hydroxy.
  • the invention provides a compound of the formula ##STR7## wherein: R 1 is alkyl, alkoxy, hydroxy, cycloalkyl, hydroxyalkyl, alkoxyalkyl or hydroxyalkoxy;
  • Y is alkylene of 3 to 9 carbon atoms
  • R 2 and R 3 independently are hydrogen, alkyl, alkoxy, halo, trifluoromethyl or nitro;
  • R 4 is alkoxy, hydroxy, halomethyl, dihalomethyl, trihalomethyl, cycloalkyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, alkanecarbonyloxyalkyl, cyano, 2,2,2-trifluoroethyl, (4-methylphenyl)sulfonyloxymethyl, N ⁇ Q or CON ⁇ Q, where N ⁇ Q is amino, alkylamino or dialkylamino; or a pharmaceutically-acceptable acid-addition salt thereof.
  • the invention provides a compound of the formula ##STR8## wherein Y, R 2 and R 3 are as defined above and R 6 is alkoxy, fluoromethyl, difluoromethyl, trihalomethyl, cycloalkyl or alkoxyalkyl.
  • the invention provides a compound of the formula ##STR9## wherein R 2 and R 3 are as defined above and R 7 is alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, cycloalkyl, alkoxyalkyl or cyano.
  • the invention provides compounds of formulas XVII and XXI hereinafter.
  • the invention provides a composition for combatting picornaviruses which comprises an antivirally effective amount of a compound of formula I in admixture with a suitable carrier or diluent and to methods for combatting picornaviruses therewith including combatting a picornaviral infection in a mammalian host.
  • the compounds of formula I are useful as antipicornaviral agents.
  • Preferred compounds of formula I are those wherein
  • R 1 is C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy, cyclopropyl, hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 1-3 -alkyl or hydroxy-C 1-3 -alkoxy;
  • Y is alkylene of 3 to 9 carbon atoms, especially 3 to 5 carbon atoms;
  • R 2 and R 3 independently are hydrogen, C 1-3 -alkyl, C 1-3 -alkoxy or halo;
  • R 4 is C 1-3 -alkoxy, hydroxy, halomethyl, dihalomethyl, trihalomethyl, cyclopropyl, C 1-3 -alkoxycarbonyl, hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 1-3 -alkyl, (C 1-3 -alkane)carbonyloxy-C 1-3 -alkyl, cyano, 2,2,2-trifluoroethyl, 4-(methylphenyl)sulfonyloxymethyl, N ⁇ Q or CON ⁇ Q, where N ⁇ Q is amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)amino.
  • More preferred compounds of formula I are compounds of the formula ##STR10## wherein R 1 , Y, R 2 , R 3 and R 4 are as defined above for formula I and especially wherein R 1 , Y, R 2 , R 3 and R 4 are as defined in the previous paragraph for the preferred compounds of formula I.
  • R 4 is C 1-3 -alkoxy, fluoromethyl, dihalomethyl, trihalomethyl, cycloalkyl or C 1-3 -alkoxy-C 1-3 -alkyl, especially trifluoromethyl.
  • alkyl, alkane, alkoxy, cycloalkyl and halo each has the following meaning:
  • alkyl and alkoxy mean aliphatic radicals, including branched radicals, of from one to five carbon atoms.
  • alkyl moiety of such radicals include, for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl and pentyl;
  • alkane means a monovalent aliphatic radical, including branched radicals of from one to four carbon atoms.
  • alkane moiety of such radical includes, for example, methyl, ethyl, propyl, isopropyl, n-butyl and sec-butyl;
  • cycloalkyl means an alicyclic radical having from three to six carbon atoms as illustrated by cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
  • halo means bromo, chloro, iodo or fluoro.
  • hydroxyalkyl and alkoxyalkyl the hydroxy and alkoxy groups can occur at any available position of alkyl.
  • hydroxyalkyl and alkoxyalkyl include, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxyisopropyl, 2, 3, 4 and 5-hydroxypentyl and the like and corresponding alkyl ethers thereof.
  • hydroxyalkoxy the hydroxy group can occur at any available position of alkoxy other than the C-1 position.
  • hydroxyalkoxy includes, for example, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxyisopropoxy, 2 and 5-hydroxypentoxy and the like.
  • the amidoxime V is reacted with the acid halide or the acid anhydride in the presence of an organic or inorganic base, e.g., pyridine, triethylamine or potassium carbonate, in an inert solvent, e.g., acetone, methylene chloride, chloroform, toluene or tetrahydrofuran, or in a base which also functions as the solvent, e.g., pyridine, at an elevated temperature (about 40°-130° C.) or at a reduced temperature (about 0°-15° C.).
  • an organic or inorganic base e.g., pyridine, triethylamine or potassium carbonate
  • an inert solvent e.g., acetone, methylene chloride, chloroform, toluene or tetrahydrofuran
  • a base which also functions as the solvent e.g., pyridine
  • an intermediate O-acyl derivative [C(NH 2 ) ⁇ NOC( ⁇ O)--(R 4 or OR)] is isolated and heated at a temperature in the range of about 100°-130° C. for a time sufficient for cyclization to the oxadiazole of formula I to occur, generally about 5 minutes to 4 hours.
  • the amidoxime V is reacted with the acid halide or acid anhydride in an acid which corresponds to the acid halide or acid anhydride at an elevated temperature (about 70°-100° C.).
  • R 1 is alkyl, alkoxy, cycloalkyl or alkoxyalkyl
  • Y, R 2 and R 3 are as defined hereinbefore
  • R 4 is dihalomethyl, trihalomethyl, cycloalkyl, alkoxyalkyl, alkanecarbonyloxyalkyl or 2,2,2-trifluoroethyl
  • R 4 is dihalomethyl, trihalomethyl, cycloalkyl, alkoxyalkyl, alkanecarbonyloxyalkyl or 2,2,2-trifluoroethyl
  • N,N'-carbonyldiimidazole prepared as described in the examples, in an inert solvent, e.g., tetrahydrofuran, chloroform, methylene chloride or toluene, at an elevated temperature (about 40°-80° C.) to form the corresponding compound of formula I.
  • R 1 is alkyl, alkoxy, cycloalkyl or alkoxyalkyl, Y, R 2 and R 3 are as defined hereinbefore, and R 4 is amino
  • R 4 is amino
  • a base e.g., potassium or sodium bicarbonate
  • an alcoholic solvent e.g., ethyl alcohol
  • amidoxime V and ketene 1,3-propanedithiol acetal are reacted in the presence of silver trifluoroacetate in an inert solvent, e.g., tetrahydrofuran, dioxane, dimethylformamide or N-methylpyrrolidinone, at a temperature in the range of from about 60° to about 100° C.
  • an inert solvent e.g., tetrahydrofuran, dioxane, dimethylformamide or N-methylpyrrolidinone
  • the intermediate amidoxime V is prepared according to the following flow sheet: ##STR14##
  • the bromophenol VI reacts with the cuprous cyanide in an inert solvent at an elevated temperature, e.g., in dimethylformamide at reflux temperature to give the cyanophenol VII.
  • the latter is reacted with haloisoxazole VIII, where X 2 is chloro, bromo or iodo, in a dry inert solvent, e.g., acetonitrile or N-methylpyrrolidinone, in the presence of a base, e.g., potassium carbonate or sodium hydroxide, optionally in the presence of a catalytic amount of potassium or sodium iodide, at an elevated temperature (50°-120° C.) to give cyano compound IX.
  • a dry inert solvent e.g., acetonitrile or N-methylpyrrolidinone
  • the cyano compound IX reacts with the hydroxylamine hydrochloride in the presence of a base, e.g. potassium or sodium carbonate, sodium acetate or sodium hydroxide, in an alcoholic solvent, e.g., ethyl alcohol, at an elevated temperature (50°-150° C.) to give the amidoxime V.
  • a base e.g. potassium or sodium carbonate, sodium acetate or sodium hydroxide
  • an alcoholic solvent e.g., ethyl alcohol
  • Certain intermediate compounds of formula IX wherein R 1 is alkyl, cycloalkyl or alkoxyalkyl and Y, R 2 and R 3 are as defined hereinbefore can be prepared by reacting the ethinyl compound XII described hereinafter with a nitrile oxide, R 1 C.tbd.N ⁇ O, where R 1 is as defined above in this paragraph, using a procedure similar to that described hereinafter for the preparation of compound I from the ethinyl compound III.
  • the intermediate bromophenols of formula VI and cyanophenols of formula VII belong to generically known classes of compounds and are readily prepared by known procedures.
  • the intermediate haloisoxazoles of formula VIII can be prepared by the procedure described in U.S. Pat. No. 4,843,087, i.e., by reacting an alkali metal derivative of an isoxazole of the formula ##STR15## wherein R 1 is alkyl, alkoxy, trifluoromethyl, cycloalkyl or alkoxyalkyl, with a dihalide, X 2 --Y'--X 2 , where Y' is alkylene of 2 to 8 carbon atoms and X 2 is as defined above.
  • the alkali metal derivative is prepared in situ by treating isoxazole X with an organo-alkali metal base such as butyllithium or lithium diisopropylamide under anhydrous conditions.
  • R 1 is alkyl, cycloalkyl or alkoxyalkyl, Y, R 2 and R 3 are as defined hereinbefore, and R 4 is alkoxy, trihalomethyl, cycloalkyl, alkoxycarbonyl, alkoxyalkyl or 2,2,2-trifluoroethyl
  • R 4 is alkoxy, trihalomethyl, cycloalkyl, alkoxycarbonyl, alkoxyalkyl or 2,2,2-trifluoroethyl
  • R 4 is alkoxy, trihalomethyl, cycloalkyl, alkoxycarbonyl, alkoxyalkyl or 2,2,2-trifluoroethyl
  • hydroxyimino halides which may also be prepared in situ, belong to a generically known class of compounds and are readily prepared by conventional procedures, e.g., by reacting the corresponding aldehyde oxime (R 1 C ⁇ NOH) with a halogenating agent, e.g., N-chlorosuccinimide or bromine.
  • a halogenating agent e.g., N-chlorosuccinimide or bromine.
  • the process for preparing the compounds of formula I by reacting the ethinyl compound of formula III takes place by heating the reactants in an inert polar solvent, e.g., dimethylformamide or N-methylpyrrolidone, at a temperature in the range of about 20° to about 120° C.
  • cyanophenol VII is reacted with haloalkyne XI, where X 2 is as defined hereinbefore, using a procedure similar to that described above for the preparation of the cyano compound IX from compounds VII and VIII, to give the ethinyl compound of formula XII.
  • Ethinyl compound XII is reacted with the hydroxylamine hydrochloride, using a procedure similar to that described above for the preparation of amidoxime V from cyano compound IX, to give the amidoxime of formula XIII.
  • amidoxime XIII is reacted with the acid halide R 4 COX, acid anhydride (R 4 CO) 2 O, carboxylic acid R 4 CO 2 H or ##STR17## using procedures similar to those described hereinbefore for the preparation of compounds of formula I from amidoxime V.
  • haloalkynes of formula XI belong to a generically known class of compounds.
  • the intermediate haloisoxazole VIII can be prepared as described hereinbefore.
  • the intermediate phenols of formula IV can be prepared by reacting cyanophenol VII with hydroxylamine hydrochloride, using a procedure similar to that described hereinbefore for the preparation of amidoxime V from cyano compound IX, to give an amidoxime of the formula ##STR18##
  • Amidoxime XIV is reacted with R 4 COX, (R 4 CO) 2 O, R 4 CO 2 H or ##STR19## using procedures similar to those described hereinbefore for the preparation of compounds of formula I from amidoxime V, to give the corresponding phenol of formula IV.
  • R 1 is hydroxyalkyl, Y, R 2 and R 3 are as defined hereinbefore, and R 4 is dihalomethyl, trihalomethyl, cycloalkyl, alkoxyalkyl, 2,2,2-trifluoroethyl or amino
  • R 1 ' is tert -butyldimethylsilyloxyalkyl [(CH 3 ) 3 CSi(Me) 2 -O-alkyl] and Y, R 2 , R 3 and R 4 are as defined above in this paragraph, by cleaving the tert-butyldimethylsilyl ether.
  • Cleavage of the tert-butyldimethylsilyl ether is carried out by treating compound XVII with strong organic acid, e.g., acetic acid or trifluoroacetic acid, or inorganic acid, e.g., hydrochloric acid or sulfuric acid, in an inert solvent, e.g., tetrahydrofuran or dioxane in the presence of water at a temperature in the range of from about 20° to about 60° C.
  • strong organic acid e.g., acetic acid or trifluoroacetic acid
  • inorganic acid e.g., hydrochloric acid or sulfuric acid
  • an inert solvent e.g., tetrahydrofuran or dioxane
  • the compound of formula XVII where R 4 is dihalomethyl, trihalomethyl, cycloalkyl, alkoxyalkyl or 2,2,2trifluoroethyl can be prepared by a process which comprises reacting phenol IV wherein R 2 and R 3 are as defined hereinbefore and R 7 is as defined above in this paragraph for R 4 , with an isoxazole of the formula ##STR21## wherein R 1 ', Y and X 2 are as defined hereinbefore.
  • the phenol IV is reacted with haloisoxazole XVI using a procedure similar to that described hereinbefore the preparation of cyano compound IX from cyanophenol VII and haloisoxaozle VIII.
  • the phenol IV is reacted with isoxazole XV in the presence of diethyl azodicarboxylate (DEAD) and triphenylphosphine in an inert solvent, e.g., tetrahydrofuran, chloroform, dimethylformamide or N-methylpyrrolidinone, at a temperature in the range of from about -20° to about 20° C.
  • DEAD diethyl azodicarboxylate
  • triphenylphosphine in an inert solvent, e.g., tetrahydrofuran, chloroform, dimethylformamide or N-methylpyrrolidinone, at a temperature in the range of from about -20° to about 20° C.
  • the intermediate phenol IV can be prepared by the procedure described hereinbefore.
  • the intermediate isoxazoles XV and XVI can be prepared by reacting isoxazole X, wherein R 1 is hydroxyalkyl, with tert-butyldimethylsilyl chloride to give the corresponding tert-butyldimethylsilyl ether of formula ##STR22## where R 1 ' is as defined above, and reaction of an alkali metal derivative of compound XVIII with ethylene oxide or X 2 --Y'--X 2 respectively.
  • Isoxazole X wherein R 1 is hydroxyalkyl, is reacted with tert-butyl(dimethyl)silyl chloride in the presence of 4 (dimethylamino)pyridine and a base, e.g., triethylamine, pyridine or imidazole, in a dry inert solvent., e.g., methylene chloride, chloroform or tetrahydrofuran, at room temperature to give compound XVIII.
  • a base e.g., triethylamine, pyridine or imidazole
  • Isoxazole XV is prepared by reacting an alkali metal derivative of compound XVIII with ethylene oxide, preferably in the presence of a chelating agent, e.g., N,N,N',N'-tetramethylethylenediamine or hexamethyl phosphoric triamide, in a dry inert solvent, e.g., tetrahydrofuran, at a temperature in the range of from about -78° to about 20° C.
  • a chelating agent e.g., N,N,N',N'-tetramethylethylenediamine or hexamethyl phosphoric triamide
  • a dry inert solvent e.g., tetrahydrofuran
  • reaction of compound XV or XVI with cyanophenol VII to give compound XIX is carried out by procedures similar to those described hereinbefore for preparing compound XVII by reacting phenol IV with isoxazole XV or haloisoxazole XVI respectively.
  • R 1 is hydroxy, Y, R 2 and R 3 are as defined hereinbefore, and R 4 is cycloalkyl or alkoxyalkyl
  • R 8 is alkyl and Y, R 2 , R 3 and R 4 are as defined above in this paragraph, with hydroxylamine hydrochloride to give the compound of formula I where R 1 is hydroxy.
  • Compound XXI is reacted with hydroxylamine hydrochloride in the presence of a base, e.g., sodium hydroxide, and water in an alcoholic solvent, e.g., methyl or ethyl alcohol, at a temperature in the range of from about 0° to about 25° C.
  • a base e.g., sodium hydroxide
  • an alcoholic solvent e.g., methyl or ethyl alcohol
  • the intermediate compounds of formula XXI can be prepared by reacting an alkali metal derivative of compound III, wherein R 6 is as defined for R 4 of compound XXI, with an alkyl haloformate, R 8 OCOX, where X is as defined hereinbefore.
  • the reaction takes place in a dry inert solvent, e.g., tetrahydrofuran or dioxane, at an initial temperature of about -78° to about -20° C. with subsequent warming to about 20° to about 25° C.
  • the alkali metal derivative can be prepared in situ by reacting compound III with an organo-alkali metal, e.g., butyllithium or lithium diisopropylamide, under anhydrous conditions.
  • the compound of formula I wherein R 1 is alkyl, trifluoromethyl, cycloalkyl or alkoxyalkyl, Y, R 2 , R 3 are as defined hereinabove, and R 4 is alkoxy or N ⁇ Q, where N ⁇ Q is alkylamino or dialkylamino, can be prepared from the corresponding compound of formula I wherein R 4 is trichloromethyl.
  • the trichloromethyl compound is reacted with an alkali metal alkoxide, e.g., sodium methoxide or sodium ethoxide, and in the case where R 4 is N ⁇ Q, with an amine(N ⁇ Q), in a suitable solvent, e.g., dimethylformamide or N-methylpyrrolidinone, at room temperature to give the corresponding compound of formula I where R 4 is alkoxy, alkylamino or dialkylamino.
  • an alkali metal alkoxide e.g., sodium methoxide or sodium ethoxide
  • R 4 is N ⁇ Q
  • a suitable solvent e.g., dimethylformamide or N-methylpyrrolidinone
  • R 1 is hydroxyalkyl, Y, R 2 and R 3 are as defined hereinbefore, and R 4 is hydroxy, dihalomethyl, trihalomethyl, cycloalkyl, hydroxyalkyl, 2,2,2-trifluoroethyl or amino
  • R 4 is hydroxy, dihalomethyl, trihalomethyl, cycloalkyl, hydroxyalkyl, 2,2,2-trifluoroethyl or amino
  • R 1 is alkoxyalkyl by ether cleavage of the alkoxyalkyl moiety.
  • the alkoxyalkyl compound is treated with trimethylsilyl iodide in a dry inert solvent, e.g., 1,2-dichloroethane, chloroform or acetonitrile, at a temperature in the range of from about 60° to about 80° C. to give the corresponding hydroxyalkyl compound.
  • a dry inert solvent e.g., 1,2-dichloroethane,
  • R 1 is alkyl, alkoxy, trifluoromethyl, cycloalkyl or alkoxyalkyl, Y, R 2 and R 3 are as defined hereinbefore, and R 4 is CON ⁇ Q, where N ⁇ Q is amino, alkylamino or dialkylamino, can be prepared by reacting the corresponding compound of formula I wherein R 4 is alkoxycarbonyl with amine N ⁇ Q in a polar solvent, e.g., ethyl alcohol or N-methylpyrrolidinone, at room temperature to give the corresponding compound where R 4 is CON ⁇ Q.
  • a polar solvent e.g., ethyl alcohol or N-methylpyrrolidinone
  • the compound of formula I where R 1 is alkyl, alkoxy, trifluoromethyl, cycloalkyl or alkoxyalkyl, Y, R 2 and R 3 are as defined hereinbefore, and R 4 is cyano, can be prepared from the corresponding compound wherein R 4 is CON ⁇ Q, where N ⁇ Q is amino, by treating the latter with trifluoroacetic anhydride in the presence of a base, e.g., pyridine or triethylamine, in a dry inert solvent, e.g., tetrahydrofuran, chloroform or 1,2-dichloroethane, at a temperature in the range of from about 0° to about 20° C.
  • a base e.g., pyridine or triethylamine
  • a dry inert solvent e.g., tetrahydrofuran, chloroform or 1,2-dichloroethane
  • R 1 is alkoxy or hydroxyalkoxy
  • Y, R 2 and R 3 are as defined above
  • R 4 is alkoxy, trihalomethyl, cycloalkyl, alkoxyalkyl, 2,2,2-trifluoroethyl or dialkylamino
  • the etherification takes place by reacting the hydroxy compound with an alkyl halide or hydroxyalkyl halide, where halide is bromide, chloride or iodide, in the presence of a base, e.g., potassium carbonate or sodium carbonate, in an inert dry solvent, e.g., acetone, butanone or acetonitrile, at a temperature in the range of from about 50° to about 90° C.
  • a base e.g., potassium carbonate or sodium carbonate
  • an inert dry solvent e.g., acetone, butanone or acetonitrile
  • the compounds of formula I wherein R 1 is alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl or hydroxyalkoxy, Y, R 2 and R 3 are as defined hereinbefore, and R 4 is hydroxyalkyl can be prepared by transesterification of the corresponding compound of formula I wherein R 4 is alkanecarbonyloxyalkyl.
  • the transesterification is carried out by treating the alkanecarbonyloxyalkyl compound with an inorganic or organic base, e.g., potassium carbonate, sodium bicarbonate or triethylamine, in an alcoholic solvent, e.g., methyl or ethyl alcohol, at room temperature.
  • the compounds of formula I wherein R 1 is alkyl, cycloalkyl or hydroxyalkyl, Y, R 2 and R 3 are as defined hereinbefore, and R 4 is hydroxyalkyl can also be prepared by ether cleavage of the corresponding compound of formula I wherein R 4 is alkoxyalkyl.
  • the ether cleavage can be carried out by treating the alkoxy compound with trimethylsilyl iodide using a procedure similar to that described hereinbefore for preparing the compound of formula I wherein R 4 hydroxyalkyl.
  • the compound of formula I wherein R 1 is alkyl, alkoxy, cycloalkyl, hydroxyalkyl, alkoxyalkyl or hydroxyalkoxy, Y, R 2 and R 3 are as defined hereinbefore, and R 4 is iodomethyl, can be prepared from the corresponding compound of formula I wherein R 4 is chloromethyl by reaction with alkali metal iodide, e.g., sodium iodide. The reaction takes place by treating the chloromethyl compound with the alkali metal iodide, e.g., sodium or potassium iodide, in an inert solvent, e.g., acetone or butanone, at about 20° C.
  • alkali metal iodide e.g., sodium or potassium iodide
  • the compounds of formula I are sufficiently basic to form stable acid-addition salts with strong acids and such salts are within the purview of the invention.
  • the nature of the acid-addition salt is immaterial, provided it is derived from an acid the anion of which is essentially non-toxic to animal organisms.
  • Appropriate acid-addition salts include hydrochloride, hydrobromide, sulfate, acid sulfate, maleate, citrate, tartrate, methanesulfonate, p-toluenesulfonate, dodecyl sulfate and cyclohexanesulfonate.
  • the acid-addition salts are prepared by conventional methods known in the art.
  • the reactions should be carried out for a time sufficient to provide the desired product and that for any specific reaction type, the time of the reaction will depend upon one or more factors such as, e.g., the nature of the reactants, the solvent employed and/or the temperature at which the reaction is carried out.
  • the antiviral compounds of the invention are formulated for use by preparing a dilute solution or suspension in a pharmaceutically acceptable aqueous, organic or aqueous-organic medium for topical or parenteral administration by intravenous or intramuscular injection, or for intranasal or ophthalmic application; or are prepared in tablet, capsule, or aqueous suspension form with conventional excipients for oral administration.
  • the structures of the compounds of the invention were established by modes of synthesis and elementary analysis, and by infrared, nuclear magnetic resonance and/or mass spectra.
  • Trichloroacetic acid (22.8 g, 140 mmol) was added to the product of Example 1d (10.6 g, 34.8 mmol) and heated at 85° C. until a thick solution was obtained.
  • Trichloroacetyl chloride (14.5 mL, 69.6 mmol) was added in three equal portions. A vigorous reaction ensued after addition of the first portion. The mixture was heated an additional hour at 94° C. The cooled mixture was diluted with water and extracted with ethyl acetate (3 ⁇ 25 mL). The combined organic phases were washed with saturated sodium bicarbonate, brine, dried (MgSO 4 ) and concentrated in vacuo to give 10.1 g of orange oil. Chromatography (Silica Gel 60, methylene chloride) provided 6.94 g of yellow oil which was crystallized from methanol to give 5.03 g of pure title compound as white needles, mp 77°-77.5° C.
  • Example 12 Dichloroacetic acid (1.24 mL, 15.0 mmol) was added to the product of Example 1d (1.14 g, 3.76 mmol) and heated at 85° C. until a solution was obtained.
  • Dichloroacetic anhydride (1.14 mL, 7.52 mmol) was added dropwise rapidly and stirred at 85° C. for an additional hour.
  • Work-up as described for Example 12 provided 1.51 g of yellow-brown oil which was purified by chromatography (Silica Gel 60, 25% ethyl acetate in hexanes) to give 1.37 g (91.3%) of pure title compound as a pale yellow oil which solidified upon standing, mp 52°-3° C. (ethanol).
  • Example 12 The product of Example 12 (627 mg, 1.46 mmol) was added to a freshly prepared solution of sodium methoxide in methanol (1.5 equivalents sodium in 5 mL methanol) in dry dimethylformamide (3-5 mL) and the mixture was stirred at room temperature for 15-30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate (3 ⁇ ). The combined organic extracts were washed with water, brine, dried (MgSO 4 ) and concentrated in vacuo.
  • Example 12 Following the procedure of Example 16 but using sodium ethoxide in ethanol in place of sodium methoxide in methanol there was obtained from the product of Example 12 (905 mg, 2.10 mmol) a crude residue (0.82 g) which was purified by chromatography (Silica Gel 60, 2% ethyl acetate in methylene chloride) to give 0.52 g (69%) of pure title compound as a yellow solid, mp 70°-72.5° C. (ethanol).
  • Example 12 The product of Example 12 (1.00 g, 2.32 mmol) was added to 5 ml of 40% aqueous methylamine in dimethylformamide (3-5 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 ⁇ ). The combined organic extracts were washed with water, brine, dried (MgSO 4 ) and concentrated in vacuo. The crude residue (0.54 g) was purified by chromatography (Silica Gel 60, first with 2% methanol in methylene chloride and then with 50% ethyl acetate in hexanes) to give 300 mg (37.5%) of pure title compound as a yellow solid, mp 126.5°-127° C. (ethanol).
  • Example 12 Following the procedure of Example 18 but using 40% aqueous dimethylamine in place of 40% aqueous methyl amine and reducing the reaction time to 15-30 minutes, there was obtained from the product of Example 12 (0.97 g, mmol) a crude residue (0.75 g) which was purified by chromatography (Silica Gel 60, 50% ethyl acetate/hexanes) give 0.70 g (84%) of pure title compound as a pale yellow solid, mp 123°-124° C. (ethanol).
  • Example 1c Following the procedure of Example 1c and using 14.7 g (100 mmol) of 3,5-dimethyl-4-hydroxybenzonitrile and substituting 5-chloro-1-pentyne (12.7 mL, 120 mmol) for the product of Example 1b, there was obtained a red-brown oil which was purified by chromatography (Silica Gel 60, 15% ethyl acetate in hexanes) to give pure title compound (21.2 g, 99.4%) as a pale yellow oil.
  • N-chlorosuccinimide N-chlorosuccinimide (NCS, 1.8-2.5 equivalents) in dry N,N-dimethylformamide or N-methylpyrrolidinone (1.6-3.0 mL per mmol NCS) and 1-2 drops of pyridine was added dropwise a solution of oxime (1.8-2.5 equivalents) in the same solvent (0.40-0.80 mL per mmol oxime). The internal temperature was maintained at 25°-30° C. with a 25° C. water bath. After 1 hour at room temperature, a solution of the appropriate ethinyl compound (formula III or XII) (1 equivalent) in the same solvent (0.80 mL per mmol the ethinyl compound) was added.
  • the reaction mixture was heated to 85°-90° C. and a solution of triethylamine (TEA, 1.8-2.5 equivalents) in the same solvent (0.80-1.6 mL per mmol TEA) was added dropwise over 45-90 minutes. After an additional hour at 85°-90° C., the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3 ⁇ ). The combined organic phases were washed with 10% KHSO 4 , water, brine, dried (MgSO 4 or Na 2 SO 4 ) and concentrated in vacuo. The crude product was purified by chromatography (Silica Gel 60, 15-40% ethyl acetate in hexanes).
  • Example 24 To a chilled (0° C.) solution of the appropriate aldehyde oxime (2.5 equivalents) in dry dimethylformamide (DMF) (15 mL) was added in 1 portion N-chlorosuccinimide (NCS) (2.5 equivalents). After 1-2 hours, the product from Example 24 (1 equivalent) was added and the whole heated to 80° C. A solution of triethylamine (2.5 equivalents) in dry DMF (5 mL) was added dropwise over 90 minutes. The mixture was heated an additional 18 hours. Work up and purification as described for Example 21 provided the pure product.
  • DMF dry dimethylformamide
  • NCS N-chlorosuccinimide
  • Example 30b Following a procedure similar to that of Example 1c but substituting the product from Example 30b (1.0 g, 3.9 mmol) for 3,5-dimethyl-4-hydroxybenzonitrile and 5-(3-methylisoxazol-5-yl)pentyl bromide (1.0 g, 4.3 mmol) for 3-(3-methylisoxazol-5-yl)propyl chloride and using 0.72 g (4.3 mmol) of potassium iodide there was obtained 0.25 g (16%) of pure title compound as a white solid, mp 41°-42° C. (methanol).
  • Example 31b Following a procedure similar to that of Example 1c but substituting the product from Example 31b (0.93 g, 3.1 mmol) for 3,5-dimethyl-4-hydroxybenzonitrile and 5-(3-methylisoxazol-5-yl)pentyl bromide (1.0 g, 4.3 mmol) for 3-(3-methylisoxazol-5-yl)propyl chloride and using 0.72 g (4.3 mmol) of potassium iodide there was obtained 0.83 g (60%) of pure title compound as a white solid, mp 42°-43° C. (hexanes).
  • Example 32b Following a procedure similar to that of Example 1c but substituting the product of Example 32b (0.42 g, 1.8 mmol) for 3,5-dimethyl-4-hydroxybenzonitrile and using 0.63 g (4.0 mmol) of the product of Example 1b and 0.67 g (4.0 mmol) of potassium iodide there was obtained, after trituration in cold methanol, 0.48 g (76%) of pure title compound as a white powder, mp 68°-69° C. (methylene chloride-hexanes).
  • Example 36b A mixture of the product of Example 36b (0.30 g, 0.85 mmol), dry acetone (25 mL), finely divided potassium carbonate (0.24 g, 1.7 mmol), and ethyl iodide (0.18 mL, 2.2 mmol) was heated at 50° C. for 18 hours, filtered, and concentrated in vacuo to give a pinkish solid. Chromatography (Silica Gel, 50% ethyl acetate in hexanes) provided 0.19 g of slightly impure title compound and 0.12 g (37%) of a pure side product (the corresponding 2,3-dihydro-2-ethyl-3-oxoisoxazole compound) as a colorless oil. Pure title compound was obtained by chromatography (reverse silica gel, 20% water in methanol); yield 0.14 g (43%), mp 70°-1° C. (methanol).
  • Example 7 Finely divided product of Example 7 (3.08 g, 8.00 mmol) was added to 10% ethanolic ammonia (80 mL). After 15 minutes, a solution was obtained and a fine precipitate started to form. After 4 hours, the mixture was filtered and the solids obtained washed with cold ethanol to give 2.35 g (82.5%) of pure title compound as a fine white powder, mp 177°-8° C. (isopropyl acetate).
  • the red solid obtained (1.67 g) was chromatographed (Silica Gel 60, 20% ethyl acetate in hexanes) to give 1.38 g (90.8%) of pure title compound as a white solid, mp 93°-4° C. (ethyl acetate and hexanes).
  • Example 1d A mixture of the product of Example 1d (4.55 g, 15.0 mmol), dry tetrahydrofuran (45 mL), 2-trifluoroethylidene-1,3 -dithiane (3.60 g, 18.0 mmol), and silver trifluoroacetate (7.3 g, 33 mmol) was refluxed in the dark for 22 hours, cooled to room temperature, and filtered. The green filter cake was washed with ethyl acetate (4 ⁇ 20 mL). The combined filtrates were concentrated in vacuo.
  • Example 20a Following the procedures of Example 20a, b and c and using equivalent amounts of reactants in each case but substituting in Example 20a 11-chloro-1-undecyne for 5-chloro-1-pentyne there can be obtained successively the following:
  • Biological evaluation of representative compounds of formula I has shown that they possess antiviral activity. They are useful in inhibiting virus replication in vitro and are primarily active against picornaviruses, especially rhinoviruses.
  • the in vitro testing of the representative compounds of the invention against picornaviruses showed that viral replication was inhibited at minimum inhibitory concentrations (MIC) ranging from 0.002 to 9.608 micrograms per milliliter.
  • MIC minimum inhibitory concentrations
  • the MIC values were determined by an automated tissue culture infectious dose 50% (TCID-50) assay.
  • HeLa (Wisconsin) cells in 96-well cluster plates were infected with a dilution of virus which had been shown empirically to produce 80% to 100% cytopathic effect (CPE) in 3 days in the absence of drug.
  • CPE cytopathic effect
  • the compound to be tested was serially diluted through 10, 2-fold cycles and added to the infected cells. After a 3 day incubation at 33° C. and 2.5% carbon dioxide, the cells were fixed with a 5% solution of glutaraldehyde followed by staining with a 0.25% solution of crystal violet in water.
  • the plates were then rinsed, dried, and the amount of stain remaining in the well (a measure of intact cells) was quantitated with an optical density reader.
  • the MIC was determined to be the concentration of compound which protected 50% of the cells from virus-induced CPE relative to an untreated virus control.

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US07/869,287 1992-04-15 1992-04-15 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents Expired - Lifetime US5349068A (en)

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US07/869,287 US5349068A (en) 1992-04-15 1992-04-15 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents
TW082102383A TW239140B (enrdf_load_html_response) 1992-04-15 1993-03-31
CZ93597A CZ285845B6 (cs) 1992-04-15 1993-04-07 1,2,4-Oxadiazolylfenoxyalkylisoxazoly a jejich použití jako protivirových prostředků
MYPI93000665A MY110191A (en) 1992-04-15 1993-04-10 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents
SG1996008085A SG50663A1 (en) 1992-04-15 1993-04-13 1,2,4-Oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents
PT93201058T PT566199E (pt) 1992-04-15 1993-04-13 1,2,4-oxadiazolil-fenioxialquilizoxazoles e suas utilizacoes como agentes antivirais
ES93201058T ES2143487T3 (es) 1992-04-15 1993-04-13 1,2,4-oxadiazolil-fenoxialquilisoxazoles y su empleo como agentes antivirales.
AT93201058T ATE189958T1 (de) 1992-04-15 1993-04-13 1,2,4-oxadiazolyl-phenoxyalkyl-isoxazole und ihre anwendung als antivirale mittel
EP93201058A EP0566199B1 (en) 1992-04-15 1993-04-13 1,2,4-Oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents
DE69327913T DE69327913T2 (de) 1992-04-15 1993-04-13 1,2,4-Oxadiazolyl-Phenoxyalkyl-isoxazole und ihre Anwendung als antivirale Mittel
DK93201058T DK0566199T3 (da) 1992-04-15 1993-04-13 1,2,4-oxadiazolyl-phenoxyalkylisoxazoler og deres anvendelse som antivirale midler
CA002094012A CA2094012C (en) 1992-04-15 1993-04-14 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents
NO19931366A NO302700B1 (no) 1992-04-15 1993-04-14 1,2,4-oksadiazolylfenoksyalkylisoksazoler preparater inneholdende disse forbindelsene og deres anvendelse for fremstilling av antivirale midler
RU93004675A RU2114112C1 (ru) 1992-04-15 1993-04-14 1,2,4-оксадиазолилфеноксиалкилизоксазолы и композиция против пикорновирусов
KR1019930006244A KR100314158B1 (ko) 1992-04-15 1993-04-14 1,2,4-옥사디아졸릴-페녹시알킬이소옥사졸및항바이러스제로서의그의용도
PH46044A PH30454A (en) 1992-04-15 1993-04-14 1,2,4-Oxadiazolyl-phenoxy-alkyl-isoxazoles and their use as antiviral agents
IL10537293A IL105372A (en) 1992-04-15 1993-04-14 1, 2, 4-Oxadiazolyl- phenoxyalkyl isoxazoles and pharmaceutical compositions containing them
HU9301084A HU220606B1 (hu) 1992-04-15 1993-04-14 (1,2,4-Oxadiazolil-fenoxi-alkil)-izoxazol-származékok, eljárás ezek előállítására és az ezeket tartalmazó vírusellenes készítmények
AU36881/93A AU666528B2 (en) 1992-04-15 1993-04-14 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents
MX9302169A MX9302169A (es) 1992-04-15 1993-04-14 Fenoxialquilisoxazolas de 1,2,4-oxadiazolilo y su uso como agentes antivirales.
NZ247411A NZ247411A (en) 1992-04-15 1993-04-15 Oxadiazolyl phenoxyalkylisoxazole derivatives and their use as antiviral agents
SK353-93A SK279786B6 (sk) 1992-04-15 1993-04-15 1,2,4-oxadiazolylfenoxyalkylizoxazoly, farmaceutic
JP05088647A JP3103845B2 (ja) 1992-04-15 1993-04-15 １，２，４−オキサジアゾリルフェノキシアルキルイソオキサゾール類及び抗ウイルス薬としてのそれらの用途
FI931707A FI112229B (fi) 1992-04-15 1993-04-15 Menetelmä uusien, terapeuttisesti käyttökelpoisten 1,2,4-oksadiatsolyyli-fenoksialkyyli-isoksatsolien valmistamiseksi
UA93003099A UA35557C2 (uk) 1992-04-15 1993-06-15 Похідні 1,2,4-оксадіазолілфеноксіалкілізоксазолу, що мають противірусну активність та фармацевтична композиція на їх основі
US08/131,050 US5464848A (en) 1992-04-15 1993-10-01 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents
US08/444,795 US5643929A (en) 1992-04-15 1995-05-19 1,2,4-oxidiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents
HU95P/P00642P HU211320A9 (en) 1992-04-15 1995-06-30 1,2,4-oxadiazolyc-phenoxyalkylisoxazoles and their use as antiviral agents
GR20000401183T GR3033486T3 (en) 1992-04-15 2000-05-24 1,2,4-Oxadiazolyl-phenoxyalkylisoxazoles and their use a s antiviral agents.

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US5643929A (en) * 1992-04-15 1997-07-01 Sanofi Winthrop, Inc. 1,2,4-oxidiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents
WO1995031452A1 (en) * 1994-05-13 1995-11-23 Sanofi Winthrop, Inc. Therapeutic phenoxyalkylazoles and phenoxyalkylazines
US7078403B1 (en) 1999-06-18 2006-07-18 Biota Scientific Management Pty Ltd. Antiviral agents
US7829705B2 (en) 2000-12-18 2010-11-09 Biota Scientific Management Pty. Ltd. Antiviral agents
US7579465B2 (en) 2000-12-18 2009-08-25 Biota Scientific Managment Pty. Ltd. Antiviral agents
US8624025B2 (en) 2000-12-18 2014-01-07 Biota Scientific Management Pty Ltd Antiviral agents
US7166604B2 (en) 2000-12-18 2007-01-23 Biota Scientific Management Pty Ltd Antiviral agents
US20070149531A1 (en) * 2000-12-18 2007-06-28 Biota Scientific Management Pty. Ltd. Antiviral agents
US20070149530A1 (en) * 2000-12-18 2007-06-28 Biota Scientific Management Pty. Ltd. Antiviral agents
US8217171B2 (en) 2000-12-18 2012-07-10 Biota Scientific Management Pty. Ltd. Antiviral agents
US20110212966A1 (en) * 2000-12-18 2011-09-01 Biota Scientific Management Pty Ltd Antiviral agents
US20090030000A1 (en) * 2000-12-18 2009-01-29 Biota Scientific Management Pty. Ltd. Antiviral agents
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US20090291990A1 (en) * 2001-08-29 2009-11-26 Gerald Rhodes Oxadiazolyl-phenoxyalkylisoxazoles, compositions thereof and methods for their use as anti-picornaviral agents
US7585884B2 (en) 2001-08-29 2009-09-08 Viropharma Incorporated Oxadiazolyl-phenoxyalkylisoxazoles, compositions thereof and methods for their use as anti-picornaviral agents
US20050043542A1 (en) * 2001-08-29 2005-02-24 Gerald Rhodes Oxadiazolyl-phenoxyalkylisoxazoles, compositions thereof and methods for their use as anti-picornaviral agents
US20080293783A1 (en) * 2001-08-29 2008-11-27 Gerald Rhodes Oxadiazolyl-phenoxyalkylisoxazoles, compositions thereof and methods for their use as anti-picornaviral agents
US7429606B2 (en) * 2001-08-29 2008-09-30 Viropharma Incorporated Oxadiazolyl-phenoxyalkylisoxazoles, compositions thereof and methods for their use as anti-picornaviral agents
US20050027127A1 (en) * 2001-08-29 2005-02-03 Diana Guy D. Oxadiazolyl-phenoxyalkylisoxazoles compositions thereof and methods for their use as anti-picornaviral agents
US11952387B2 (en) 2018-08-21 2024-04-09 Kyorin Pharmaceutical Co., Ltd Bicyclic heteroaromatic ring derivative

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